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Engineered Cell-Membrane-Coated Nanoparticles Directly Present Tumor Antigens to Promote Anticancer Immunity.

ABSTRACT: The recent success of immunotherapies has highlighted the power of leveraging the immune system in the fight against cancer. In order for most immune-based therapies to succeed, T cell subsets with the correct tumor-targeting specificities must be mobilized. When such specificities are lacking, providing the immune system with tumor antigen material for processing and presentation is a common strategy for stimulating antigen-specific T cell populations. While straightforward in principle, experience has shown that manipulation of the antigen presentation process can be incredibly complex, necessitating sophisticated strategies that are difficult to translate. Herein, the design of a biomimetic nanoparticle platform is reported that can be used to directly stimulate T cells without the need for professional antigen-presenting cells. The nanoparticles are fabricated using a cell membrane coating derived from cancer cells engineered to express a co-stimulatory marker. Combined with the peptide epitopes naturally presented on the membrane surface, the final formulation contains the necessary signals to promote tumor antigen-specific immune responses, priming T cells that can be used to control tumor growth. The reported approach represents an emerging strategy that can be used to develop multiantigenic, personalized cancer immunotherapies.

SUBMITTER: Jiang Y

PROVIDER: S-EPMC7669572 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Engineered Cell-Membrane-Coated Nanoparticles Directly Present Tumor Antigens to Promote Anticancer Immunity.

Jiang Yao Y Krishnan Nishta N Zhou Jiarong J Chekuri Sanam S Wei Xiaoli X Kroll Ashley V AV Yu Chun Lai CL Duan Yaou Y Gao Weiwei W Fang Ronnie H RH Zhang Liangfang L

Advanced materials (Deerfield Beach, Fla.) 20200615 30

The recent success of immunotherapies has highlighted the power of leveraging the immune system in the fight against cancer. In order for most immune-based therapies to succeed, T cell subsets with the correct tumor-targeting specificities must be mobilized. When such specificities are lacking, providing the immune system with tumor antigen material for processing and presentation is a common strategy for stimulating antigen-specific T cell populations. While straightforward in principle, experi ...[more]

PMID: 32538494

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Project description:BackgroundA number of immunotherapeutic approaches have been developed and are entering the clinic. Bispecific antibodies (BsAbs) are one of these modalities and induce robust efficacy by endogenous T cells in several hematological malignancies. However, most of the treated patients experience only a temporary benefit. Currently available BsAbs provide only anti-CD3 antibody-mediated T-cell stimulation, but not the costimulation or cytokine signaling essential for full T-cell activation. Here, we hypothesized that the simultaneous input of more comprehensive signals would elicit more robust and durable effector T-cell functions.MethodsWe genetically engineered the leukemia cell line K562 to express BsAbs, costimulatory ligands, cytokines, and blocking antibodies against immune checkpoint molecules on the cell surface, from which we obtained plasma membrane fractions by mechanical homogenization and subsequent isolation steps. Plasma membranes were reconstituted on the poly (lactic-co-glycolic acid) surface to generate membrane-coated nanoparticles (NPs). Alternatively, nano-sized membrane vesicles (MVs) were generated by ultrasonic dispersion of the isolated membranes. The antitumor function of NPs and MVs loaded with various immunomodulatory factors was evaluated in vitro and in vivo.ResultsBoth membrane-coated NPs and MVs induced BsAb-mediated antigen-specific cytotoxic activity in non-specific T cells, with MVs inducing a slightly better response in vivo. Importantly, T-cell activation was elicited only in the presence of target tumor cells, providing a safety advantage for clinical use. NPs and MVs expressing costimulatory molecules (CD80/4-1BBL) and cytokines (interleukin (IL)-7/IL-15) further enhanced effector T-cell function and induced therapeutic efficacy in vivo. In addition, MVs expressing immune checkpoint antibodies and inflammatory cytokines IL-12 and IL-18 induced objective antitumor responses in solid tumor models partly by converting immunosuppressive macrophages to proinflammatory phenotypes and inducing cytotoxic T-cell infiltration into the tumor. Finally, we showed that MVs were also engineered to activate natural killer (NK) cells by loading multiple ligands. MVs loaded with BsAbs, 4-1BBL, IL-15, and IL-21 induced NK-cell cytotoxic activity in an antigen-specific manner.ConclusionsWe developed antitumor NPs and MVs that efficiently induced antitumor immune responses in vivo by simultaneously delivering multiple immunostimulatory signals to endogenous T cells. This platform enables the delivery of desired combinations of antitumor immune signals into T cells and NK cells.

Dataset Information

Engineered Cell-Membrane-Coated Nanoparticles Directly Present Tumor Antigens to Promote Anticancer Immunity.

Publications

Engineered Cell-Membrane-Coated Nanoparticles Directly Present Tumor Antigens to Promote Anticancer Immunity.

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